Them bones them bones them dry bones – and how to help repair them

THIS BLOG IS ALSO AVAILABLE AS AN AUDIOCAST ON SPOTIFY

Broken bones

People say that with age comes wisdom, kindness and confidence. What they usually don’t say is that it also comes with aches and pains and problems we didn’t have when we were younger. For example, as we get older our bones get thinner and more likely to break and less likely to heal properly.

That’s a depressing opening paragraph isn’t it. But don’t worry, things get better from here because new research from Germany has found clues as to what causes our bones to become more brittle, and what we can do to try and stop that.

Researchers at the Max Planck Institute for Biology of Ageing and CECAD Cluster of Excellence for Ageing Research at the University of Cologne have identified changes in stem cells from our bone marrow that seem to play a key role in bones getting weaker as we age.

To explain this we’re going to have to go into the science a little, so bear with me. One of the issues the researchers focused on is the role of epigenetics, this is genetic information that doesn’t change the genes themselves but does change their activity. Think of it like a light switch. The switch doesn’t change the bulb, but it does control when it’s on and when it’s off. So this team looked at the epigenome of MSCs, the stem cells found in the bone marrow. These cells play a key role in the creation of cartilage, bone and fat cells.

In a news release, Dr. Andromachi Pouikli, one of the lead researchers in the study, says these MSCs don’t function as well as we get older.

“We wanted to know why these stem cells produce less material for the development and maintenance of bones as we age, causing more and more fat to accumulate in the bone marrow. To do this, we compared the epigenome of stem cells from young and old mice. We could see that the epigenome changes significantly with age. Genes that are important for bone production are particularly affected.”

So, they took some stem cells from the bone marrow of mice and tested them with a solution of sodium acetate. Now sodium acetate has a lot of uses, including being used in heating pads, hand warmers and as a food seasoning, but in this case the solution was able to make it easier for enzymes to get access to genes and boost their activity.

“This treatment impressively caused the epigenome to rejuvenate, improving stem cell activity and leading to higher production of bone cells,” Pouikli said.

So far so good. But does this work the same way in people? Maybe so. The team analyzed MSCs from people who had undergone hip surgery and found that they showed the same kind of age-related changes as the cells from mice.

Clearly there’s a lot more work to do before we can even think about using this finding as a solution to aging bones. But it’s an encouraging start.

The study is published in the journal Nature Aging.

Using a stem cell’s journey to teach kids science

THIS BLOG CAN ALSO BE HEARD AS AN AUDIOCAST ON SPOTIFY

As far as Aldo Pourchet is concerned you are never too young to learn about stem cells. Aldo should know. He’s a molecular and cellular biologist and the co-founder and CEO of Omios Bio, which develops immunotherapies for cancer, infectious and inflammatory diseases.

Aldo Pourchet

And now Aldo is the author of a children’s book about stem cells. The book is “Nano’s Journey! A Little Stem Cell Visits the Heart and Lungs.” It’s the story of Nano, a stem cell who doesn’t know what kind of cell she wants to be when she grows up, so she goes on a journey through the body, exploring all the different kinds of cell she could be.

It’s a really sweet book, beautifully illustrated, and written in a charming way to engage children between the ages of 5 and 8. I asked Aldo what made him want to write a book like this.

“I was interested in providing very general knowledge such as the principle of life, the basic logics of nature and at the same time to entertain. It was very important for it not to be a textbook.

“Why Stem cells? Because it is the most fascinating biology and they are at the origin of an organism and throughout its life play an essential role. They evolve and transform, so they have a story that unfolds. An analogy with children maybe. It’s easy to imagine children are like stem cells, trying to decide who they are, while adults are like differentiated cells because they have already decided.

“For the kids to appropriate the story, I thought that humanizing cells was important.  I wanted children to identify themselves with the cells and especially Nano, the little girl main character. It’s a book written for the children, in the first place. We tell the story at their level. Not try to bring them up to the level of life science.

Aldo says right from the start he had a clear idea of who he wanted the lead character to be.

“I think the world needs more female leaders, more female voices and influence in general and in every domain. So quite early it became natural for me that Nano would be a girl and also would have a strong character, curious and adventurous.

“Blasto came later because I was looking for a companion to share the adventure with Nano. Blasto is a fibroblast so he is not supposed to leave the Bone Marrow but fibroblasts are everywhere in our organism so I thought it was an acceptable stretch.

The drawings in the book are delightful, colorful and fun. Aldo says he had some ideas, rounded shapes for the cells for example and a simple design that reflected the fact that there are no lines in nature. Illustrator Jen Yoon took it from there:

“Based on Aldo’s direction and imagination, I envisioned the style like drawings on a chalkboard. Soft curves with rough textures. After that everything went smoothly. Following Nano’s journey with my iPad pencil, it felt like a boat ride at an amusement park.”

The books are written to be read aloud by parents, adults and teachers to kids. But, spoiler alert, we don’t find out what cell Nano decides to be in this book. She’s going to have more adventures in other books before she makes up her mind.

Stem cell therapy for diabetic foot ulcers shows promise in new study

For individuals with diabetes, the body’s inability to properly control blood sugar levels can lead to a wide range of other problems as time passes. One major issue is a diabetic foot ulcer (DFU), an open sore or wound that is commonly located on the bottom of the foot and caused by poor blood circulation and nerve damage. It occurs in approximately 15% of individuals with diabetes and in severe cases can lead to foot or leg amputation. Unfortunately, there is usually no effective form of treatment for this condition.

However, results from several studies authorized by the Ministry of Health of Nicaragua showed that using a stem cell therapy to treat patients with DFUs was safe and could be beneficial to patients.

The first results in a pilot study after an 18-month period demonstrated safety of the therapy and complete wound healing by nine months. After the six-year mark, five of the initial 10 subjects still demonstrated persistence of clinical benefits. It should be noted that five had passed away due to cardiac and other non-study-related causes.

In another study, the team wanted to determine the safety and efficacy of the stem cell therapy to treat non-healing DFUs greater than 3 centimeters in diameter.

For this clinical trial, 63 people from 35 to 70 years old with Type 2 diabetes and chronic DFU, all of whom were amputation candidates, were treated with a mixture of various types of stem cells obtained from the patient’s own fat tissue. The stem cell therapy was injected directly into the DFU with the hopes of restoring damaged blood vessels and promoting blood circulation and healing.

Patients were seen six months post treatment to evaluate ulcer closure, with 51 patients achieving 100 percent DFU closure and eight having greater than 75 percent. Only three required early amputations and one patient died. At 12 months post treatment, 50 patients had 100 percent DFU healing, while four had greater than 85 percent healing.

In a news release, Dr. Anthony Atala, Director of the Wake Forest Institute for Regenerative Medicine, expressed interest in evaluating this stem cell therapy and results further.

“This work should be reviewed as it demonstrates the possibility of a novel cell injection therapy that can alleviate pain and infection, accelerate wound healing, and possibly avoid amputation.”

The full results of the recent study were published in Stem Cells Translational Medicine.

Meet xenobots 2.0 – the next generation of living robots

Xenobots scurry about and can work together in swarms.
Source: Doug Blackiston

Last year we wrote about how researchers at the University of Vermont and Tufts University were able to create what they call xenobots – the world’s first living, self healing robots created from frog stem cells.

Now, the same team has created an upgraded version of these robots that they have dubbed Xenobots 2.0. These upgraded robots have the ability to self-assemble a body from single cells, do not require muscle cells to move, and demonstrate the capability to record memory. In comparison to the previous version developed, Xenobots 2.0 can move faster, navigate different environments, have longer lifespans, and still have the ability to work together in groups and heal themselves if damaged. 

To create Xenobots 2.0, researchers at Tufts University took stem cells from embryos from the African frog Xenopus laevis (which is where the name Xenobots is derived from). The team then allowed the stem cells to self assemble and grow into sphere-like shapes. In a few days, these newly formed stem cell spheroids produced tiny hair-like projections, allowing them to move back and forth or rotate in a specific way.

Meanwhile, scientists at the University of Vermont were running computer simulations that modeled different shapes of the Xenobots to see if they might exhibit different behaviors, both individually and in groups. The team ran hundreds of thousands of random environmental conditions using an evolutionary algorithm and used these simulations to identify the Xenobots most able to work together in swarms to gather large piles of debris in a field of particles. What they found was that Xenobots 2.0 are much faster and better at tasks such as garbage collection. They can also cover large flat surfaces or travel through narrow capillaries.

Using a fluorescent protein, Xenobots 2.0 record exposure to blue light by turning green. Source: Doug Blackiston

Going one step further for Xenobots 2.0, the researchers at Tufts University engineered the Xenobots in a way to enable them to record one bit of information. By introducing a fluorescent protein, they were able to get the Xenobots to glow green normally. However, if the Xenobots were exposed to blue light, they would start to glow red instead.

To test this memory function, the team allowed ten Xenobots to swim around a surface on which one spot is illuminated with a beam of blue light. After two hours, they found that three bots glowed red and the rest remained green, effectively recording their travel experience.

In a press release, robotics expert Josh Bongard from the University of Vermont who played an integral role in this study elaborated on what these findings could implicate.

“When we bring in more capabilities to the bots, we can use the computer simulations to design them with more complex behaviors and the ability to carry out more elaborate tasks. We could potentially design them not only to report conditions in their environment but also to modify and repair conditions in their environment.”

Xenobots 2.0 were also able to heal quite rapidly, closing the majority of a deep cut half their thickness within 5 minutes of the injury. All injured bots were able to ultimately heal the wound, restore their shape, and continue their work as before.

In the same press release, Dr. Michael Levin, professor at Tufts University and corresponding author of the study, had this to say.

“The biological materials we are using have many features we would like to someday implement in the bots – cells can act like sensors, motors for movement, communication and computation networks, and recording devices to store information. One thing the Xenobots and future versions of biological bots can do that their metal and plastic counterparts have difficulty doing is constructing their own body plan as the cells grow and mature, and then repairing and restoring themselves if they become damaged. Healing is a natural feature of living organisms, and it is preserved in Xenobot biology.”

The full results of this study were published in Science Robotics.

You can learn more about this research from Dr. Michael Levin by watching his TED Talk linked below:

New hydrogel developed could aid in therapies to generate bones in head and neck

Taking a cue from mussels’ natural ability to adhere to surfaces underwater, the UCLA researchers incorporated an alginate-based solution in their hydrogel.
Photo taken by D. Jude, Univ. of Michigan

When most people think of mussels, what immediately comes to mind might be a savory seafood dish or favorite seafood restaurant. But to Dr. Alireza Moshaverinia and his team of researchers at the UCLA School of Dentistry, it’s the ability that mussels have to stick to wet surfaces that is of particular interest.

Partially inspired by this concept and with support from CIRM, the team of researchers developed the first adhesive hydrogel specifically to regenerate bone and tissue defects following head and neck injuries.

Over the past few years, surgeons and clinicians have began to use hydrogels to administer stem cells to help regenerate lost tissues and for bone defects. Hydrogels are beneficial because they can be effective at carrying stem cells to targeted areas inside the body. However, when used in surgeries of the mouth, they tend to become less effective because blood and saliva prevent them from properly adhering to the targeted site. As a result of this, the stem cells don’t stay in place long enough to deliver their regenerative properties.

To help with this problem, the researchers at UCLA developed a new hydrogel by adding alginate into the mix. Alginates are found in the cells of algae and form a sticky, gum-like substance when wet.

The scientists then tested their new hydrogel by loading it with bone building stem cells and applying it to the mouths of rats with an infectious disease that affects the bone structure. They then sealed the hydrogel in place and applied a light treatment, similar to what dentists use in humans to solidify dental fillings.

The results showed that the bone around the implants in all of the rats had completely regenerated.

In a news release from UCLA, Dr. Moshaverinia elaborates on what this study means for potential future treatments.

“The light treatment helped harden the hydrogel, providing a more stable vehicle for delivery of the stem cells. We believe that our new tissue engineering application could be an optimal option for patients who have lost their hard and soft craniofacial tissues due to trauma, infection or tumors.”

The full study was published in Science Translational Medicine.

Tiny organs grown from snake stem cells produce real venom

Researchers grew tiny venom glands from nine different snake species, including the cape coral cobra pictured above.
Photo Credit: Michael D. Kern/Science Source

Snake venom can be deadly without proper treatment. Interestingly enough, it may also hold the key for treatments against pain, high blood pressure, and cancer according to one analysis. Despite this, scientists still do not understand much about the biology behind the wide range of different snake venoms, which can make it challenging to develop effective treatments in the event of snake bites.

Fortunately, a new study by Dr. Hans Clevers and his team at the Hubrecht Institute in the Netherlands could significantly aid the understanding of snake venom. Dr. Clevers and his team were able to grow miniature snake venom glands using snake stem cells. What’s more remarkable is that these “mini-organs” produced real venom!

Miniature, lab-grown snake venom glands
 Photo Credit: Ravian van Ineveld/Princess Maxima Center

In an article posted in Science Magazine, Dr. Clevers talks about how his study was navigating uncharted waters.

“Nobody knew anything about stem cells in snakes. We didn’t know if it was possible at all.”

To produce these “mini-organs”, the researchers removed the stem cells from the venom glands of nine different types of snake and placed them in a mixture of growth factors that contained different hormones and proteins. It turns out that the snake stem cells responded to the same factors used on human and mouse stem cells.

Eventually, the stem cells grew into little clumps of tissue and when the researchers removed the growth factors, they started to change into the same kind of cells that produce venom in the glands of snakes. Additionally, they were able to find that these “mini-organs” expressed similar genes as those observed in real venom glands.

The scientists were even able to test the nature of the “mini-organ” venom as well. A chemical and genetic analysis of the venom revealed that it matched the one made by real snakes. After testing this venom on mouse muscle cells and rat neurons, they also found that it damaged these cells similar to real venom.

The type of toxins and concentration levels can vary drastically in snake venom, even within the same species. This can make developing treatments challenging since they can only be used to combat one type of venom.

Dr. Clevers and his team now plan to study the complexities of venom and venom glands by compiling a “biobank” of frozen organoids from venomous reptiles around the world that could help researchers find broader treatments. With the aid of their newly developed “mini-organs”, all of this can be done without the handling of live, dangerous snakes, some of which are rare and difficult to keep in captivity.

The full results of this study were published in Cell.

Two studies identify a molecule that could be used to block Zika virus and kill cancer cells

Dr. Tariq Rana (left) and Dr. Jeremy Rich (right) both lead independent teams at UC San Diego that identified a molecule, αvβ5 integrin, as the Zika virus’ key to getting into brain stem cells

Zika virus is caused by a virus transmitted by Aedes mosquitoes. People usually develop mild symptoms that include fever, rash, and muscle and joint pain. However, Zika virus infection during pregnancy can lead to much more serious problems. The virus causes infants to be born with microcephaly, a condition in which the brain does not develop properly, resulting in an abnormally small head. In 2015-2016, the rapid spread of the virus was observed in Latin America and the Caribbean, increasing the urgency of understanding how the virus affected brain development.

Working independently, Dr. Tariq Rana and Dr. Jeremy Rich from UC San Diego identified the same molecule, αvβ5 integrin, as the Zika virus’ key to entering brain stem cells. The two studies, with the aid of CIRM funding, discovered how to take advantage of the molecule in order to block the Zika virus from infecting cells. In addition to this, they were able to turn it into something useful: a way to destroy brain cancer stem cells.

In the first study, Dr. Rana and his team used CRISPR gene editing on brain cancer stem cells to delete individual genes, which was done to see which genes are required for the Zika virus to enter the cells. They discovered that the gene responsible for αvβ5 integrin also enabled the Zika virus.

In a press release by UC San Diego, Dr. Rana elaborates on the importance of his findings.

“…we found Zika uses αvβ5, which is unique. When we further examined αvβ5 expression in brain, it made perfect sense because αvβ5 is the only integrin member enriched in neural stem cells, which Zika preferentially infects. Therefore, we believe that αvβ5 is the key contributor to Zika’s ability to infect brain cells.”

In the second study, Dr. Rich and his team use an antibody to block αvβ5 integrin and found that it prevented the virus from infecting brain cancer stem cells and normal brain stem cells. The team then went on to block αvβ5 integrin in a mouse model for glioblastoma, an aggressive type of brain tumor, by using an antibody or deactivating the gene responsible for the molecule. Both approaches blocked Zika virus infection and allowed the treated mice to live longer than untreated mice. 

Dr. Rich then partnered with Dr. Alysson Muotri at UC San Diego to transplant glioblastoma tumors into laboratory “mini-brains” that can be used for drug discovery. The researchers discovered that Zika virus selectively eliminates glioblastoma stem cells from the mini-brains. Additionally, blocking αvβ5 integrin reversed that anti-cancer activity, further demonstrating the molecule’s crucial role in Zika virus’ ability to destroy cells.

In the same UC San Diego press release, Dr. Rich talks about how understanding Zika virus could help in treating glioblastoma.

“While we would likely need to modify the normal Zika virus to make it safer to treat brain tumors, we may also be able to take advantage of the mechanisms the virus uses to destroy cells to improve the way we treat glioblastoma.”

Dr. Rana’s full study was published in Cell Reports and Dr. Rich’s full study was published in Cell Stem Cell.

Stories of the week – preterm birth and mice with a human immune system

While we are here at ISSCR 2019 hearing various scientists talk about their work, we realize that there are various breakthroughs in stem cell research in a wide variety of different fields going on every day. It is wonderful to see how scientists are hard at work in developing the latest science and pushing innovation. Here are two remarkable stories you may have missed this week.

Scientists developing way to help premature babies breathe easier

Researchers at Cincinnati Children’s Hospital Medical Center are looking at ways to stimulate lung development in premature infants who suffer from a rare condition called Bronchopulmonary Dysplasia (BPD), which can cause lifelong breathing problems and even death. Using a mouse model of BPD, extensive analysis, and testing, the scientists were able to create a proposal to develop a stem cell therapy based on what are called c-KIT endothelial progenitor cells.

Premature babies, unable to breathe on their own, rely on machines to help them breathe. Unfortunately, these machines can interfere with lung development as well. The cells proposed in the stem cell therapy are common in the lungs of infants still in the womb and help in the formation of capillaries and air sacs in the lungs called alveoli.

In a press release, Dr. Vlad Kalinichenko, lead investigator for this work, was quoted as saying,

“The cells are highly sensitive to injury by high oxygen concentrations, so lung development in premature babies on mechanical oxygen assistance is impeded. Our findings suggest using c-KIT-positive endothelial cells from donors, or generating them with pluripotent stem cells, might be a way to treat BPD or other pediatric lung disorders associated with loss of alveoli and pulmonary microvasculature.”

The full results were published in American Journal of Respiratory and Critical Care Medicine.

Mice with a human immune system help research into cancer and infections

Speaking of a mouse model, researchers from Aarhus University and Aarhus University Hospital have succeeded in using mice with a transplanted human immune system to study functions in the immune system which are otherwise particularly difficult to study. This work could open the possibilities towards looking further into disease areas such as cancer, HIV, and autoimmune diseases.

Before potential treatments can be tested in humans, there needs to be extensive animal testing and data generated. However, when the disease relate’s to the human immune system, it can be particularly challenging to evaluate this in mice. The research team succeeded in transplanting human stem cells into mice whose own immune system is disabled, and then triggered a type of reaction in the immune system which normally reacts to meeting a range of viruses and bacteria.

In a press release, Dr. Anna Halling Folkmar, one of the researchers behind the study, says that,

“The humanised mice are an important tool in understanding how human immune cells behave during diseases and how they react to different medical treatments.”

The full results were published in Immunology.

From organs to muscle tissue: how stem cells are being used in 3D

A Sunday Afternoon on the Island of La Grande Jatte by Georges-Pierre Seurat

When most people think of stem cells, they might conjure up an image of small dots under a microscope. It is hard to imagine these small specs being applied to three-dimensional structures. But like a pointillism painting, such as A Sunday Afternoon on the Island of La Grande Jatte by Georges-Pierre Seurat, stem cells can be used to help build things never thought possible. Two studies demonstrate this concept in very different ways.

MIT engineers have designed coiled “nanoyarn,” shown as an artist’s interpretation here. The twisted fibers are lined with living cells and may be used to repair injured muscles and tendons while maintaining their flexibility. Image by Felice Frankel

A study at MIT used nanofiber coated with muscle stem cells and mesenchymal stem cells in an effort to provide a flexible range of motion for these stem cells. Hundreds of thousands of nanofibers were twisted, resembling yarn and rope, in order to mimic the pattern found in tendons and muscle tissue throughout the body. The researchers at MIT found that the yarn like structure of the nanofibers keep the stem cells alive and growing, even as the team stretched and bent the fibers multiple times.

Normally, when a person injures these types of tissues, particularly around a major joint such as the shoulder or knee, it require surgery and weeks of limited mobility to heal properly. The MIT team hopes that their technology could be applied toward treating the site of injury while maintaining range of motion as the newly applied stem cells continue to grow to replace the injured tissue.

In an article, Dr. Ming Guo, assistant professor of mechanical engineering at MIT and one of the authors of the study, was quoted as saying,

“When you repair muscle or tendon, you really have to fix their movement for a period of time, by wearing a boot, for example. With this nanofiber yarn, the hope is, you won’t have to wearing anything like that.”

Their complete findings were published in the Proceedings of the National Academy of Sciences (PNAS).

Researchers in Germany have created transparent human organs using a new technology that could pave the way to print three-dimensional body parts such as kidneys for transplants. Above, Dr. Ali Ertuerk inspects a transparent human brain.
Photo courtesy of Reuters.

In a separate study, researchers in Germany have successfully created transparent human organs, paving the way to print three-dimensional body parts. Dr. Ali Erturk at Ludwig Maximilians University in Munich, with a team of scientists, developed a technique to create a detailed blueprint of organs, including blood vessels and every single cell in its specific location. These directions were then used to print a scaffold of the organ. With the help of a 3D printer, stem cells, acting like ink in a printer, were injected into the correct positions to make the organ functional.

Previously, 3D-printed organs lacked detailed cellular structures because they were based on crude images from computer tomography or MRI machines. This technology has now changed that.

In an article, Dr. Erturk is quoted as saying,

“We can see where every single cell is located in transparent human organs. And then we can actually replicate exactly the same, using 3D bioprinting technology to make a real functional organ. Therefore, I believe we are much closer to a real human organ for the first time now.”

Stem Cell Agency Awards Almost $4 Million to Develop a Treatment for Spinal Degeneration

Today the governing Board of the California Institute for Regenerative Medicine (CIRM) awarded $3.9 million to Ankasa Regenerative Therapeutics for a promising approach to treat a degenerative condition that can cause chronic, progressive back pain.

As we get older, the bones, joints and ligaments in our back become weak and less able to hold the spinal column in alignment.  As a result, an individual vertebral bone in our spine may slip forward over the one below it, compressing the nerves in the spine, and causing lower back pain or radiating pain.  This condition, called degenerative spondylolisthesis, primarily affects individuals over the age of 50 and, if left untreated, can cause intense pain and further degeneration of adjacent regions of the spine.

Current treatment usually involves taking bone from one of the patient’s other bones, and moving it to the site of the injury.  The transplanted bone contains stem cells necessary to generate new bone.  However, there is a caveat to this approach— as we get older the grafts become less effective because the stem cells in our bones are less efficient at making new bone.  The end result is little or no bone healing. 

Ankasa has developed ART352-L, a protein-based drug product meant to enhance the bone healing properties of these bone grafts.  ART352-L works by stimulating bone stem cells to  increase the amount of bone produced by the graft.

The award is in the form of a CLIN1 grant, with the goal of completing the testing needed to apply to the Food and Drug Administration (FDA) for permission to start a clinical trial in people.

This is a project that CIRM has supported through earlier phases of research.

“We are excited to see the development that this approach has made since its early stages and reflects our commitment to supporting the most promising science and helping it advance to the clinic,” says Maria T. Millan, MD, President & CEO of CIRM. “There is an unmet medical need in older patients with bone disorders such as degenerative spondylolisthesis.  As our population ages, it is important for us to invest in potential treatments such as these that can help alleviate a debilitating condition that predisposes to additional and fatal medical complications.”

See the animated video below for a descriptive and visual synopsis of degenerative spondylolisthesis.